The transfusion of T-cells (i.e. T lymphocytes), referred to as adoptive T-cell therapy, has been tested for the treatment of cancer and chronic infections. Adoptive T-cell therapy has the potential to enhance antitumor immunity, augment vaccine efficacy and limit graft-versus-host disease. Adoptive T-cell therapy uses as a cell source, inter alia, cytotoxic T-cells (CTLs), or tumor-infiltrating lymphocytes (TILs). Bispecific antibodies can be used to “arm” (activated) T-cells in order to form a bridge between them and a surface antigen on tumor cells. Bispecific antibodies that target on one side a surface marker/antigen on tumor cells and on the other side to another marker/antigen that is naturally/endogenously expressed in or on cells are described, for example, in Glorius et al., Blood 116 (2010), 1173; Rothe et al., Blood 118 (2011), 1585; Zhengxing et al., Blood 111 (2007), 2211-2219, Herrmann et al., Cancer Research 68 (2008), 1221-1227; Singer et al., Journal of Immunotherapy 33 (2010), 599-608; Brandi et al., Experimental Hematology 27 (1999), 1264-1270; James et al., European Journal of Cancer 35 (1999), S343-S344; Chen et al., Clinical Cancer Research 1 (1995), 1319-1325; Valera et al., Molecular Cancer Therapeutics 9 (2010), 1872-1883; Gelderman et al., European Journal of Immunology 36 (2006), 977-984; Schweizer et al., Cancer Immunology Immunotherapy 51 (2002), 621-629; Friedman et al., Biotechnology and Applied Biochemistry 54 (2009), 121-131; Schaefer et al., Cancer Cell 20 (2011), 472-486 and Kazuhiko et al., International Journal of Molecular Medicine 25 (2010), 209-215.
Antigen-specific cytotoxic T-cells (CTLs) are known to have the capacity to kill human cancer cells, as shown by tumor regression after adoptive transfer of ex-vivo expanded tumor infiltrating lymphocytes (TILs) or of T-cell receptor gene-transfected T-cells to patients with melanoma (Leen et al., Annu. Rev. Immunol. 115 (2007), 98-104). An alternative known approach is the use of bispecific antibodies in order to redirect large numbers of endogenous T-cells. These bispecific antibodies, some formats of which are called BiTE (for “bispecific T-cell engager”) were constructed in such a way that they target on one side the surface marker CD3 (that naturally occurs/endogenously expressed on T-cells) and on the other side a surface antigen on tumor cells (that is naturally/endogenously expressed on the surface of tumor cells). Moreover, it has been shown in previous work that anti-CD3 anti-target antigen bispecific antibodies of this particular design had an exceptionally high potency and could engage CD8+ T-cells and CD4+ T-cells for lysis of cancer cells at very low effector to target (E:T) ratios. Two BiTE antibodies are currently in clinical trials: Blinatumomab (also known as MT103) is bispecific for CD3 and CD19. It is currently being tested in a phase I trial in patients with late stage, relapsed non-Hodgkin's lymphoma (NHL) (Bargou et al., Science 321 (2008), 974-977) and in a phase II trial in patients with B-precursor acute lymphoblastic leukemia (B-ALL) (Topp et al., Blood 112 (2008), 1926). The second BiTE antibody in phase I trial is MT-110 (Micromet Inc), which targets the pan-carcinoma-associated antigen, epithelial cell adhesion molecule (EpCAM or CD326) and CD3 (Brischwein et al., Mol. Immunol. 43 (2006), 1129-1143). One bispecific antibody (catumaxumab [Removab®]; bispecific against CD3 and human EpCAM) has been approved for marketing in Europe in 2009.
In vitro and in mouse model systems bispecific antibodies are capable of connecting a T-cell and a cancer cell by simultaneously binding CD3 and a target antigen, which triggers T-cell activation involving cytotoxic granule fusion and transient cytokine and granzyme release. However, the activation of a large number of T-cells (independent of T-cell antigen specificity) and/or the bystander effect of tumor cell lysis leads to serious problems when using such bispecific antibodies, e.g., as part of a therapeutic regimen in humans.
One such problem is the so called “cytokine release syndrome (CRS)”, which in the mouse model system normally causes no effects but can have catastrophic effects in humans (Suntharalingam et al., The New England Journal of Medicine 355 (2006), 1018-1028). CRS includes headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. The most severe form leads to pulmonary infiltrates, lung injury, renal failure, and disseminated intravascular coagulation (Suntharalingam et al., The New England Journal of Medicine 355 (2006), 1018-1028). Even if CRS is not associated with bispecific antibody application, a significant number of other side effects (over 80% of toxicities of grade three or higher) has been seen after bispecific antibody administration (Topp et al., Journal of Clinical Oncology 29 (2011), 2093-2098). Such side effects are ascribed to the T-cell engagement as well and include lymphopenia, blood chemistry changes and eurologic symptoms.
Due to the high side effect profile of the bispecific antibodies it is not possible to use antibody formats with a long half-life, since in case of a CRS event the long half-life is undesirable.
Therefore, the technical problem of the present invention was the provision of means and methods for the treatment of a malignant disease such as cancer of epithelial, endothelial or mesothelial origin and cancer of the blood by the induction of T-cell mediated immune response.